Highlights d Comprehensive LUAD proteogenomics exposes multi-omic clusters and immune subtypes d Phosphoproteomics identifies candidate ALK-fusion diagnostic markers and targets d Candidate drug targets: PTPN11 (EGFR), SOS1 (KRAS), neutrophil degranulation (STK11) d Phospho and acetyl modifications denote tumor-specific markers and druggable proteins

Highlights d Integrated proteogenomic characterization in 103 ccRCC cases d Delineation of chromosomal translocation events leading to chromosome 3p loss d Tumor-specific proteomic/phosphoproteomic alterations unrevealed by mRNA analysis d Immune-based subtypes of ccRCC defined by mRNA, proteome, and phosphoproteome

The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators. Here, we combined quantitative proteomics with CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to reveal a comprehensive map of regulated acetylation sites and their dynamic turnover rates. CBP/p300 acetylates thousands of sites, including signature histone sites and a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Time-resolved acetylome analyses identified a subset of CBP/p300-regulated sites with very rapid (<30 min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions and for understanding the impact of small-molecule inhibitors targeting its catalytic and bromodomain activities.